PROJECT SUMMARY Dr. Eric Osborn is an early career faculty member at Beth Israel Deaconess Medical Center (BIDMC) and Massachusetts General Hospital (MGH), and an Instructor in Medicine at Harvard Medical School, Boston, Massachusetts. He is a graduate of the MD-PhD program at Harvard Medical School and Massachusetts Institute of Technology, and has completed clinical training in medicine and subspecialty training in cardiology at BIDMC. His goal is to become an independent physician-scientist, using innovative molecular imaging approaches to investigate the key in vivo pathobiology underlying atherothrombosis and coronary stent healing. Dr. Osborn is fully committed to a career in academic cardiology, and is pursuing an NIH K08 Career Development Award in the laboratory of his mentor, Dr. Farouc Jaffer (Cardiovascular Research Center, MGH), to gain the additional expertise necessary to develop into a successful independent investigator. Dr. Osborn's career development plan leverages the resources of a world-class environment at two leading academic institutions, BIDMC and MGH, to acquire essential new skills that will position him to answer important questions in cardiovascular disease as an independent scientist. In addition, he has surrounded himself with a group of highly experienced Scientific Advisors that are leaders in engineering, optical imaging, vascular biology, and coronary stent design ? Dr. Gary Tearney (MGH), Dr. Peter Libby (Brigham and Women's Hospital), and Dr. Elazer Edelman (Massachusetts Institute of Technology) ? and will help guide him scientifically and in his career development as he grows to independence. Dr. Osborn's research proposal aims to investigate in vivo biological mechanisms underlying abnormal coronary stent healing, to better understand, predict, and prevent stent complications, using translatable intravascular molecular-structural imaging. The stent complications of restenosis (narrowing due to scar tissue growth) and thrombosis (occlusive blood clot) are major limitations of stent technology, and lead to tens-of- thousands of repeat invasive procedures and adverse cardiovascular events each year. His research aims will leverage a novel and highly translational catheter-based intravascular imaging system developed in Dr. Jaffer's laboratory that combines near-infrared fluorescence (NIRF) molecular imaging with optical coherence tomography (OCT) microstructural imaging. In Aim 1, we will investigate mechanisms of coronary stent restenosis in experimental subjects related to in vivo NIRF protease inflammatory activity, and whether intervention with the anti-inflammatory drug colchicine can decrease restenosis by modulating stent inflammation in vivo. In Aim 2, we will define the healing response of the newest FDA-approved stents with bioabsorbable polymer coatings, promoted as safer, rapidly healing stents, using intravascular NIRF-OCT molecular-structural imaging of fibrin and stent tissue coverage. The anticipated results of these two Aims will provide significant insights into the pathobiology of stent complications, and support new treatment strategies for stent restenosis, using translatable molecular imaging. With the expert mentorship of Dr. Jaffer and support of his Scientific Advisory Committee, Dr. Osborn is poised to provide new insight into stent restenosis and thrombosis. He has already obtained key preliminary results demonstrating the feasibility of his research plan. Overall, this project will develop new intravascular molecular-structural imaging approaches to inform in vivo mechanisms of stent failure that may offer new insights to reduce stent complications worldwide. In the near term, Dr. Osborn aims to gain the necessary skills and expertise that will allow him to successfully transition to scientific independence and start his own molecular imaging research program. Further ahead, he plans to pursue a career balancing translational research applying cutting-edge advanced in vivo molecular imaging approaches to define mechanisms of atherothrombosis, vascular injury, and stent complications, in concert with a focused cardiology clinical practice. He envisions that this combination of hypothesis-driven translational research and clinical cardiology practice will enable him to develop new knowledge and approaches that can impact current paradigms for the diagnosis and treatment of coronary atherosclerosis. To achieve his goals, the NIH K08 Career Development Award is an instrumental mechanism that will ensure sufficient protected mentored research time for Dr. Osborn to develop into a successful and independent physician-scientist.